Regulation of CD8 T cell responses to polyoma virus infection

描述（由申请人提供）：持续性病毒感染是发病率和死亡率的主要原因。例如艾滋病毒（导致艾滋病）、巨细胞病毒（CMV）、。eb病毒（EBV）（导致单核细胞增多症和B细胞淋巴瘤）、丙型肝炎（导致肝脏破坏）和人类乳头瘤病毒（可能导致宫颈癌）。需要对CDS T细胞进行持续监测，以消除或至少控制这些病毒在全身的传播。理解为什么CDS T细胞不能消除持续性病毒病原体是人类健康的一个关键问题。该建议试图解决可能被证明是关键干预措施的关键因素，以倾斜有利于宿主的平衡，允许消除病毒并产生能够防止再次感染的稳定记忆CDS T细胞池。这些研究的模型是多瘤病毒（PyV），这是一种感染小鼠（天然宿主）的小型致癌DMA病毒。CDS T细胞免疫对于控制感染后肿瘤的形成和生长至关重要，并且几乎在所有组织中都可以终生检测到持续的病毒感染。该建议的第一个目的是比较pyv特异性T细胞在感染的急性和持续阶段的进化。这些研究是使用在中间T抗原中表达OVA257-264的新型重组PyV进行的。在不同的时间点进行最佳启动所需的限制或条件可能存在关键差异，而这种新型病毒将使我们能够在感染后的不同时间点使用OT-I转基因T细胞的过继转移来清楚地解决这个问题。目的2解决树突状细胞在持续期感染中启动CDS T细胞的作用。目的3涉及对共刺激分子（特别是CD27/CD70）的操纵。这种共刺激分子在记忆CDS T细胞的维持和发育中起着关键作用。在持续感染期间，将OT- I转基因T细胞过继转移，然后用可溶性CD70处理，也将对这一主题进行研究。总的来说，这些研究应该为可能的治疗干预提供关键的见解，以刺激在许多持续性病毒感染中观察到的缺陷CDS T细胞免疫。

DESCRIPTION (provided by applicant): Persistent viral infections are a major cause of morbidity and mortality. Examples include HIV (resulting in AIDS), Cytomegalqvirus (CMV),. Epstein Barr virus (EBV) (responsible for mononucleosis, and; B cell lymphoma), Hepatitis C (leading to liver destruction), and Human Papiloma Virus (which may result in cervical cancer). Continual surveillance of CDS T cells is required to eliminate or, at minimum, control the spread of these viruses throughout the body. Understanding why CDS T cells are incapable of eliminating a persistent viral pathogen is a critical concern for human health. This proposal attempts to address key factors that may prove to be critical interventions to tilt the balance in favor of the host, allowing the elimination of the virus and the generation of a stable memory CDS T cell pool capable of preventing reinfection. The model for these studies is polyoma virus (PyV), a small, oncogenic DMA virus that infects mice (the natural host). CDS T cell immunity is critical to control tumor formation and outgrowth following infection, and a persistent viral infection can be detected in almost all tissues for life. The first aim of the proposal compares the evolution of PyV-specific T cells primed during acute and persistent phases of infection. These studies are performed using a novel recombinant PyV expressing OVA257-264 within the middle T antigen. Key differences may exist in the restrictions or conditions necessary for optimal priming at different time points, and this novel virus will allow us to clearly address this question using adoptive transfer of OT-I transgenic T cells at various time points post infection. Aim 2 addresses the role of dendritic cells in the priming of CDS T cells in persistent phase infection. Aim 3 involves the manipulation of costimulatory molecules (specifically CD27/CD70). This costimulatory molecule plays a critical role in the maintenance and development of memory CDS T cells. This subaim will also be investigated with adoptive transfer of OT- I transgenic T cells followed by treatment with soluble CD70 during persistent infection. Collectively, these studies should provide critical insights into possible therapeutic interventions to stimulate defective CDS T cell immunity observed in numerous persistent viral infections.